Role of Pitx3 in the Development of Midbrain DA Neurons

Parkinson's disease (PD), one of the most common neurodegenerative diseases, is caused by the selective loss of dopaminergic (DA) neurons in the substantia nigra pars compacta (SNc). Molecular mechanisms underlying the development and maintenance of midbrain DA (mDA) neurons, especially substantia nigra DA neurons, are poorly understood. Pitx3 is an emerging transcription factor in the regulatory cascades influencing the development of SNc DA neurons. Several groups including ours have recently shown that, in Pitx3-deficient aphakia (ak) mice, DA neurons in the SNc fail to develop properly, whereas DA neurons in the ventral tegmental area (VTA) are largely unaffected. These data suggest that Pitx3 critically and selectively controls the development of SNc DA neurons, although the precise role of Pitx3 in this process is not clear. This project will study the molecular/cellular mechanisms underlying the Pitx3 function in SNc DA neuronal development. The outcome of this study will provide insights on control mechanisms of SNc neurons, which may be translated into a better understanding of the etiopathogenesis of PD and devising novel therapeutic approaches.